Ischemia-related diseases, in particular coronary artery diseases, account for the majority of deaths in the Western countries. Myocardial ischemia is a serious condition and rapid identification and location of myocardial ischemia is therefore highly desirable so that the necessary actions, e.g. therapeutic or surgical treatment, can be taken promptly before irreversible myocardial damage occurs.
Ischemic injury can be considered to result from two main events: (i) hypoxia leading to an inadequate supply of oxygen to the tissues; and (ii) decreased transport of metabolic substrates to the tissues and of metabolic end products from the tissues. Immediate consequences include energy deficit and an accumulation of protons and lactate in the region of ischemia. Other consequences include a marked, potentially harmful stimulation of the sympathetic nervous system, which ultimately leads to a rapid loss of adenosine triphosphate (ATP), an early onset of acidosis and decreased organ function.
Cardiac tissue, like other metabolically active tissues, is particularly vulnerable to ischemic injury. The initial phase of acute myocardial infarction is in general associated with a loss of normal contractile function, which manifests itself as regional dyskinesia. This may be due to an abrupt fall in coronary perfusion pressure, which induces an acute hibernating state, and to the rapid cessation of normal trans-membrane ion transport. Reperfusion of the ischemic myocardium prior to the onset of irreversible injury may lead to a rapid or delayed return (stunning) to normal cardiac metabolism and function.
Magnetic resonance imaging (MRI) has been established as a useful cardiac imaging technique. Although MR techniques using spin-echo imaging are capable of showing the anatomy of the heart, the use of contrast agents is necessary for the detection of myocardial ischemia and infarction. One class of MR contrast agents is paramagnetic contrast agents, which comprise a paramagnetic metal ion, preferably Mn2+ ion in the form of a salt or in a complex with a chelating/complexing moiety.
By intravenous infusion of a manganese contrast agent that releases divalent and paramagnetic Mn2+ ions, these ions will be easily taken up into cardiac cells and act as intracellular contrast agents. Cell uptake of Mn2+ ions occur via physiological channels in the cell membrane for calcium (Ca2+) ions which are main conductors of cell physiology and metabolism. The intracellular Mn2+ ion retention lasts for hours and Mn2+ ions induce paramagnetic effects inside the cardiac cell.
The total influx of Mn2+ ions per time unit is raised during increased heart rate and force of contraction. However, in ischemic myocardium, much less Mn2+ ions are taken up because of reduction in blood flow, mitochondrial function and metabolism and decrease in contractility. Hence ischemic myocardium can be detected and distinguished from normal myocardial tissue by MR imaging using paramagnetic Mn2+ ions as a contrast agent. Further, Mn2+ is not a substrate for Ca2+ ATPase and the Na+/Ca2+ exchanger during relaxation, and is hence retained in the heart for many hours. This “memory effect” lasts long enough to perform MR investigation in such a way, that a patient administered with a Mn2+ comprising contrast agent performs physical exercise outside the MR imager to raise heart rate and subsequent imaging is then performed up to 1 hour after administration. Another reason for using a regimen of stress is that it allows for lower doses of the contrast agent.
According to prior art, contrast agents are administered to the body before, simultaneously with or after stress. By stress is meant raising the heart rate and myocardial metabolism physically and/or pharmacologically to a maximum level, also called peak stress. After the stress procedure is completed, the body is subjected to an imaging procedure.
WO A1 2004/054623 describes a method of MR imaging where contrast agent is administered to the body and a regimen of physical and/or pharmacological stress is exposed to the body before or simultaneously to the contrast agent administration.
WO A1 2006/028380 describes a two step method and a one step method of MR imaging.
In both procedures the contrast agent should be administered to the body by slow intravenous infusion. In the two-step method the patient is exposed to stress after infusion of the contrast agent, and in the one step method stress and infusion is performed simultaneously.